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( Mei Jing Piao ),( Pattage Madushan Dilhara Jayatissa Fernando ),( Kyoung Ah Kang ),( Pincha Devage Sameera Madushan Fernando ),( Herath Mudiyanselage Udari Lakmini Herath ),( Young Ree Kim ),( Jin W 한국응용약물학회 2024 Biomolecules & Therapeutics(구 응용약물학회지) Vol.32 No.1
Rosmarinic acid (RA) is a phenolic ester that protects human keratinocytes against oxidative damage induced by ultraviolet B (UVB) exposure, however, the mechanisms underlying its effects remain unclear. This study aimed to elucidate the cell signaling mechanisms that regulate the antioxidant activity of RA and confirm its cyto-protective role. To explore the signaling mechanisms, we used the human keratinocyte cell line HaCaT and SKH1 hairless mouse skin. RA enhanced glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS) expression in HaCaT cells in a dose- and time-dependent manner. Moreover, RA induced nuclear factor erythroid-2-related factor 2 (NRF2) nuclear translocation and activated the signaling kinases protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the ERK inhibitor U0126, and small interfering RNA (siRNA) gene silencing suppressed RA-enhanced GCLC, GSS, and NRF2 expression, respectively. Cell viability tests showed that RA significantly prevented UVB-induced cell viability decrease, whereas the glutathione (GSH) inhibitors buthionine sulfoximine, LY294002, and U0126 significantly reduced this effect. Moreover, RA protected against DNA damage and protein carbonylation, lipid peroxidation, and apoptosis caused by UVB-induced oxidative stress in a concentration-dependent manner in SKH1 hairless mouse skin tissues. These results suggest that RA protects against UVB-induced oxidative damage by activating AKT and ERK signaling to regulate NRF2 signaling and enhance GSH biosynthesis. Thus, RA treatment may be a promising approach to protect the skin from UVB-induced oxidative damage.
Min Chang Oh,Pincha Devage Sameera Madushan Fernando,Mei Jing Piao,Kyoung Ah Kang,Herath Mudiyanselage Udari lakmini Herath,Jin Won Hyun 대한암예방학회 2023 Journal of cancer prevention Vol.28 No.2
Excessive UVB exposure causes development of both malignant and non-malignant melanoma via the secretion of α-melanocyte-stimulating hormone (α-MSH). We investigated whether baicalein (5,6,7-trihydroxyflavone) could inhibit α-MSH-stimulated melanogenesis. Baicalein prevented UVB- and α-MSH-induced melanin production and attenuated α-MSH-stimulated tyrosinase (monophenol monooxygenase) activity, and expression of tyrosinase and tyrosine-related protein-2. In addition, baicalein prevented melanogenesis and pigmentation via the p38 mitogen-activated protein kinases signaling pathway. These findings suggest that baicalein represents a natural compound for attenuating melanogenesis.
7,8-Dihydroxyflavone Protects High Glucose-Damaged Neuronal Cells against Oxidative Stress
조석주,강경아,Mei Jing Piao,류예성,Pincha Devage Sameera Madushan Fernando,Ao Xuan Zhen,현유재,안미정,강희경,현진원 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.1
Oxidative stress is considered a major contributor in the pathogenesis of diabetic neuropathy and in diabetes complications, such as nephropathy and cardiovascular diseases. Diabetic neuropathy, which is the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. This study aimed to investigate whether 7,8-dihydroxyflavone (7,8-DHF) protects SH-SY5Y neuronal cells against high glucose-induced toxicity. In the current study, we found that diabetic patients exhibited higher lipid peroxidation caused by oxidative stress than healthy subjects. 7,8-DHF exhibits superoxide anion and hydroxyl radical scavenging activities. High glucose-induced toxicity severely damaged SH-SY5Y neuronal cells, causing mitochondrial depolarization; however, 7,8-DHF recovered mitochondrial polarization. Furthermore, 7,8-DHF effectively modulated the expression of pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) under high glucose, thus inhibiting the activation of caspase signaling pathways. These results indicate that 7,8-DHF has antioxidant effects and protects cells from apoptotic cell death induced by high glucose. Thus, 7,8-DHF may be developed into a promising candidate for the treatment of diabetic neuropathy.
Extract of Seaweed Dictyota coriacea Scavenges Superoxide Anion and Hydroxyl Radical
MEIJING PIAO,Kyoung Ah Kang,Herath Mudiyanselage Udari Lakmini Herath,Pincha Devage Sameera Madushan Fernando,Nam Ho Lee,Jin Won Hyun 건강기능식품미래포럼 2023 건강기능식품미래포럼 학술지 Vol.3 No.2
In this study, we prepared the ethanol extract of Dictyota coriacea (DCEE) and investigated its ability, along with epiloliolide and 1,9-dihydroxycrenulide compounds derived from this seaweed, to eliminate superoxide anion (·O2 − ) and hydroxyl radical (·OH) through electron spin resonance spectrometry. The findings indicate that DCEE effectively scavenges both ·O2 − and ·OH, while the 2 compounds target ·OH only. These results support the ·OH scavenging properties of DCEE and imply the presence of substances within DCEE that can also eliminate ·O2 − . Furthermore, in order to identify ingredients with antioxidant properties and ensure their safety, we fractionated DCEE into 5 fractions using solvents of varying polarities (hexane, dichloromethane, ethyl acetate, butanol, and water) and examined these fractions for 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity and cytotoxicity. Among the 5 fractions, the ethyl acetate fraction exhibited the highest activity, followed by the water and dichloromethane fractions, while the hexane and butanol fractions displayed the lowest activities. With regards to cytotoxicity, all fractions except for the water fraction exhibited varying degrees of cytotoxic effects, which correlated inversely with the polarity of the solvents used. The ethyl acetate and dichloromethane fractions demonstrated superior scavenging activity but also higher cytotoxicity, whereas the butanol fraction exhibited lower cytotoxicity but the least scavenging activity. These findings suggest that D. coriacea possesses the ability to eliminate ·O2 − and ·OH and propose that fractionating DCEE using water may yield antioxidant ingredients with minimal cytotoxicity
Comparative Study of Autophagy in Oxaliplatin-Sensitive and Resistant SNU-C5 Colon Cancer Cells
Boo Sun-Jin,Piao Mei Jing,Kang Kyoung Ah,Zhen Ao Xuan,Fernando Pincha Devage Sameera Madushan,Herath Herath Mudiyanselage Udari Lakmini,Lee Seung Joo,Song Seung Eun,Hyun Jin Won 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.5
Few studies have evaluated the role of autophagy in the development of oxaliplatin (OXT) resistance in colon cancer cells. In this study, we compared the role of autophagy between SNU-C5 colon cancer cells and OXT-resistant SNU-C5 (SNU-C5/OXTR) cells. At the same concentration of OXT, the cytotoxicity of OXT or apoptosis was significantly reduced in SNU-C5/OXTR cells compared with that in SNU-C5 cells. Compared with SNU-C5 cells, SNU-C5/OXTR cells exhibited low levels of autophagy. The expression level of important autophagy proteins, such as autophagy-related protein 5 (Atg5), beclin-1, Atg7, microtubule-associated proteins 1A/1B light chain 3B I (LC3-I), and LC3-II, was significantly lower in SNU-C5/OXTR cells than that in SNU-C5 cells. The expression level of the autophagy-essential protein p62 was also lower in SNU-C5/OXTR cells than in SNU-C5 cells. In SNUC5/ OXTR cells, the production of intracellular reactive oxygen species (ROS) was significantly higher than that in SNU-C5 cells, and treatment with the ROS scavenger N-acetylcysteine restored the reduced autophagy levels. Furthermore, the expression of antioxidant-related nuclear factor erythroid 2-related factor 2 transcription factor, heme oxygenase-1, and Cu/Zn superoxide dismutase were also significantly increased in SNU-C5/OXTR cells. These findings suggest that autophagy is significantly reduced in SNU-C5/OXTR cells compared with SNU-C5 cells, which may be related to the production of ROS in OXT-resistant cells.
( Mei Jing Piao ),( Xia Han ),( Kyoung Ah Kang ),( Pincha Devage Sameera Madushan Fernando ),( Herath Mudiyanselage Udari Lakmini Herath ),( Jin Won Hyun ) 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.3
Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G1 cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca<sup>2+</sup> accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonin-induced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.
Niacinamide Protects Skin Cells from Oxidative Stress Induced by Particulate Matter
( Ao Xuan Zhen ),( Mei Jing Piao ),( Kyoung Ah Kang ),( Pincha Devage Sameera Madushan Fernando ),( Hee Kyoung Kang ),( Young Sang Koh ),( Joo Mi Yi ),( Jin Won Hyun ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.6
Niacinamide (NIA) is a water-soluble vitamin that is widely used in the treatment of skin diseases. Moreover, NIA displays antioxidant effects and helps repair damaged DNA. Recent studies showed that particulate matter 2.5 (PM<sub>2.5</sub>) induced reactive oxygen species (ROS), causing disruption of DNA, lipids, and protein, mitochondrial depolarization, and apoptosis of skin keratinocytes. Here, we investigated the protective effects of NIA on PM<sub>2.5</sub>-induced oxidative stress in human HaCaT keratinocytes. We found that NIA could inhibit the ROS generation induced by PM<sub>2.5</sub>, as well block the PM<sub>2.5</sub>-induced oxidation of molecules, such as lipids, proteins, and DNA. Furthermore, NIA alleviated PM<sub>2.5</sub>-induced accumulation of cellular Ca<sup>2+</sup>, which caused cell membrane depolarization and apoptosis, and reduced the number of apoptotic cells. Collectively, the findings show that NIA can protect keratinocytes from PM<sub>2.5</sub>-induced oxidative stress and cell damage.
Shilnikova Kristina,Piao Mei Jing,Kang Kyoung Ah,Fernando Pincha Devage Sameera Madushan,Herath Herath Mudiyanselage Udari Lakmini,Cho Suk Ju,Hyun Jin Won 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.2
Radiation resistance represents an imperative obstacle in the treatment of patients with colorectal cancer, which remains difficult to overcome. Here, we explored the anti-proliferative and migration-inhibiting properties of the natural product shikonin on a radiation- resistant human colon carcinoma cell line (SNU-C5RR). Shikonin reduced the viability of these cells in a dose-dependent manner; 38 μM of shikonin was determined as the half-maximal inhibitory concentration. Shikonin induced apoptotic cell death, as demonstrated by increased apoptotic body formation and the number of TUNEL-positive cells. Moreover, shikonin enhanced mitochondrial membrane depolarization and Bax expression and also decreased Bcl-2 expression with translocation of cytochrome c from mitochondria into the cytosol. In addition, shikonin activated mitogen-activated protein kinases, and their specific inhibitors reduced the cytotoxic effects of shikonin. Additionally, shikonin decreased the migration of SNU-C5RR cells via the upregulation of E-cadherin and downregulation of N-cadherin. Taken together, these results suggest that shikonin induces mitochondria-mediated apoptosis and attenuates epithelial-mesenchymal transition in SNU-C5RR cells.
( Mei Jing Piao ),( Ki Cheon Kim ),( Kyoung Ah Kang ),( Pincha Devage Sameera Madushan Fernando ),( Herath Mudiyanselage Udari Lakmini Herath ),( Jin Won Hyun ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.1
Ultraviolet B (UVB) radiation causes DNA base modifications. One of these changes leads to the generation of 8-oxoguanine (8- oxoG) due to oxidative stress. In human skin, this modification may induce sunburn, inflammation, and aging and may ultimately result in cancer. We investigated whether phloroglucinol (1,3,5-trihydroxybenzene), by enhancing the expression and activity of 8-oxoG DNA glycosylase 1 (Ogg1), had an effect on the capacity of UVB-exposed human HaCaT keratinocytes to repair oxidative DNA damage. Here, the effects of phloroglucinol were investigated using a luciferase activity assay, reverse transcription-polymerase chain reactions, western blot analysis, and a chromatin immunoprecipitation assay. Phloroglucinol restored Ogg1 activity and decreased the formation of 8-oxoG in UVB-exposed cells. Moreover, phloroglucinol increased Ogg1 transcription and protein expression, counteracting the UVB-induced reduction in Ogg1 levels. Phloroglucinol also enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) as well as Nrf2 binding to an antioxidant response element located in the Ogg1 gene promoter. UVB exposure inhibited the phosphorylation of protein kinase B (PKB or Akt) and extracellular signal-regulated kinase (Erk), two major enzymes involved in cell protection against oxidative stress, regulating the activity of Nrf2. Akt and Erk phosphorylation was restored by phloroglucinol in the UVB-exposed keratinocytes. These results indicated that phloroglucinol attenuated UVB-induced 8-oxoG formation in keratinocytes via an Akt/Erk-dependent, Nrf2/Ogg1-mediated signaling pathway.
Jin Won Hyun,Kyoung Ah Kang,장예,MEIJING PIAO,Ao Xuan Zhen,Herath Mudiyanselage Udari Lakmini Herath,Pincha Devage Sameera Madushan Fernando 건강기능식품미래포럼 2022 건강기능식품미래포럼 학술지 Vol.2 No.4
Luteolin has been reported to possess apoptotic and antitumor properties. Apoptosis induced by endoplasmic reticulum (ER) stress becomes a potential target for chemotherapeutic strategies since drug resistance develops less if anticancer action is attributed to this apoptosis. In the present study, we raised a possibility that luteolin may induce apoptosis via inducing the ER stress and attempted to test this possibility using HT-29 human colon cancer cells. When HT-29 cells were treated with luteolin, decrease of cell viability, DNA fragmentation and the increase of sub-G1 population were observed, confirming that this compound induced apoptosis. Simultaneously, the cells showed typical signs observed in the response of ER stress, which were Ca2+ overloading in cytosol and mitochondria, phosphorylation of PKR-like ER kinase (PERK) and its downstream proteins: eukaryotic initiation factor-2α and inositol requiring protein1(IRE1), splicing of ER stress-specific X-box transcription factor-1 (XBP-1), cleavage of activating transcription factor 6 (ATF6) as well as up-regulation of glucose-regulated protein-78 (GRP78) and CCAAT/enhancer-binding protein-homologous protein (CHOP). However, when HT-29 cells transfected with siCHOP RNA were treated with luteolin, its effects on decrease of cell viability, DNA fragmentation and sub-G1 population were significantly reduced, suggesting that the luteolin-induced apoptosis is mediated by inducing ER stress. These results support that luteolin has the potential as an agent for cancer prevention or treatment.